The most common forms of acquired
epilepsies arise following acute brain insults such as
traumatic brain injury,
stroke, or
central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop
epilepsy prevention
therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely
inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human
epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful
epilepsy prevention or disease modification strategies. Risk factors for developing
epilepsy that appear common to multiple acute injury etiologies include intracranial
bleeding, disruption of the blood-brain barrier, more severe injury, and early
seizures within 1 week of injury. In diverse human
epilepsies and animal models,
seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of
epilepsy of diverse and mostly focal origin are microglial activation and
astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from
temporal lobe epilepsy patients. There is increasing evidence that
epilepsy can be prevented or aborted in preclinical animal models of acquired
epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post-
status epilepticus models of
focal epilepsy by transient treatment with a trkB/PLCĪ³1 inhibitor,
isoflurane, or
HMGB1 antibodies and by
topical administration of
adenosine, in the cortical fluid percussion injury model by focal cooling, and in the
albumin posttraumatic
epilepsy model by
losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of
epilepsy after
brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention
therapy. Going forward, the identification of impending
epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.